Fei Meng, Huiyan Li, Yijie Wang, Zhiming Zheng, Yan Chen
The serine/threonine kinase AKT is a central signaling node frequently dysregulated in cancer, integrating inputs from both canonical PI3K-dependent and alternative activation pathways to drive tumorigenesis. In this review, we systematically summarize the complex regulatory mechanisms governing AKT activation, with a focus on oncogenic alterations such as PIK3CA mutations and PTEN loss. Moreover, we discuss the distinct functional contributions of AKT isoforms in cancer progression and provide a comprehensive review of how diverse post-translational modifications, including ubiquitination, methylation, SUMOylation, palmitoylation, and O-GlcNAcylation, fine-tune AKT activity, localization, and stability. Recent structural and mechanistic insights into membrane recruitment, conformational changes, and compensatory reactivation under therapeutic pressure are discussed. The review synthesizes the current challenges in targeting the AKT pathway, emphasizing the necessity for innovative strategies that address its complexity, adaptive resistance, and the potential of isoform-specific and combination therapies.